Peripheral neuropathy is one of the major complications of diabetes mellitus. Both a decrease in nerve conduction velocity and increased resistance to conduction failure caused by ischemia are among the earliest changes detected in diabetic patients and animal models of the disease. Ultrastructural studies have demonstrated changes in both axons and Schwann Cells (SC) (e.g., decrease in axon caliber and segmental demyelination) as well as in the microvasculature, all of which appear to develop independently. Some studies concluded that the progressive loss of fibers in peripheral nerves observed in human diabetic neuropathy may be due, at least in part, to delayed nerve degeneration and impaired nerve regeneration. Metabolic and microvascular abnormalities, as well as a deficiency in neurotrophins, have been considered responsible for the pathogenesis of diabetic neuropathy. The vascular alterations in diabetes consists mainly of ischemia and endoneurial hypoxia. The mechanisms underlying these vascular abnormalities include degenerative changes in the sympathetic nerve endings of vasa nervorum, with the consequent impairment in neural control of nerve blood flow and reduced production of prostacyclin and nitric oxide in nerves. Since most of these alterations are ameliorated by antioxidant therapies, it has been hypothesized that oxidative stress plays a central role in the pathogenesis of diabetic complications.
Two distinct clinical manifestations of diabetic neuropathy are those represented by patients suffering from painful symmetrical polyneuropathy, and by patients with insensitive, painless feet. There is still controversy regarding the nature of these two syndromes. The painless neuropathy is the prevalent disorder and, according to several studies, is likely to reflect the degree of nerve degeneration. The painful syndrome, on the other hand, is associated with fewer morphological abnormalities. While it has also been proposed that the painful syndrome may reflect nerve regeneration, as opposed to degeneration, several reports suggest that nerve regeneration is impaired in diabetes. Analysis of several functional indices in peripheral sensory nerves of diabetic rodents also suggests depressed, rather than increased, function. For instance, experimental diabetes induces several nociceptive responses including early thermal hyperalgesia that with time turns into hypoalgesia, mechanical hyperalgesia, thermal and tactile allodynia, increased C fiber activity and reduced sensitivity to opioids. In this context, mechanical hyperalgesia may result from increased firing after sustained suprathreshold mechanical stimulation of C fibers.
While therapies with antioxidants, vasodilators and neurotrophins may reverse some functional and metabolic abnormalities in diabetic nerves, they only result in a partial amelioration of abnormal pain perception, suggesting that other pathways are at play.